Spiro piperidine derivatives as 5HT1D receptor antagonists

ABSTRACT

Novel spiro piperdine derivatives of formula (I), in which P 1 , P 2 , R 1 , R 2 , R 2  &#39;, R 3 , m, A, E, G, X, Y, R 7 , R 8 , R 9  and R 10  have the meanings defined in claim 1 are described, as well as their use for preparing medicaments which have 5HT1D receptor antagonist activity.

This is a 371 of International Application PCT/EP96/04878, filed Nov. 5,1996.

The present invention relates to novel piperidine derivatives, processesfor their preparation and pharmaceutical compositions containing them.

EPA 0 533 266/7/8 disclose a series of benzanilide derivatives which aresaid to possess 5HT_(1D) receptor antagonlist activity. PCT/EP/95/04889discloses further 5HT_(1D) receptor antagonist having a spiropiperidinestructure. These compounds are said to be of use in treatment of variousCNS disorders. The 5HT_(1D)β receptor has now been reclassified as the5HT_(1B) receptor (P. R. Hartig et al Trends in Pharmacological Science,1996, 17, 103-105.

A structurally distinct class of compounds have now been discovered andhave been found to exhibit 5HT_(1D) antagonist activity. In a firstaspect, the present invention therefore provides a compound of formula(I) or a salt or N-oxide thereof: ##STR2## in which P¹ and P² areindependently phenyl, napthyl, a 5 to 7-membered heterocyclic ringselected from the group consisting of thienyl, furyl, pyrrolyl,triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl andpyrazinyl, or a bicyclic heterocyclic ring selected from the groupconsisting of include quinoline, isoquinoline, benzofuran andbenzothiophene;

R¹ is hydrogen, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, COC₁₋₆ alkyl, C₁₋₆alkoxy, hydroxy, hydroxyC₁₋₆ alkyl, hydroxyC₁₋₆ alkoxy, C₁₋₆ alkoxyC₁₋₆alkoxy, acyl, nitro, trifluoromethyl, cyano, SR⁹, SOR⁹, SO₂ R⁹, SO₂ NR¹⁰R¹¹, CO₂ R¹⁰, NR¹⁰ SO₂ R¹¹, CONR¹⁰ R¹¹, CO₂ NR¹⁰ R¹¹, CONR¹⁰ (CH₂)_(p)CO₂ R¹¹, (CH₂)_(p) NR¹⁰ R¹¹, (CH₂)_(p) CONR¹⁰ R¹¹, (CH₂)_(p) NR¹⁰ COR¹¹,(CH₂)_(p) CO₂ C₁₋₆ alkyl, CO₂ (CH₂)_(p) OR¹⁰, CONHNR¹⁰ R¹¹, NR¹⁰ R¹¹,N═CNR⁹ NR¹⁰ R¹¹, NR¹⁰ CO₂ R¹¹, NR¹⁰ CO(CH₂)_(p) NR¹⁰ R¹¹, NR¹⁰ CONR¹⁰R¹¹, CR¹⁰ ═NOR¹¹, CNR¹⁰ ═NOR¹¹, or NR¹² COR¹³ where R⁹, R¹⁰ and R¹¹ areindependently hydrogen or C₁₋₆ alkyl, p is 1 to 4, R¹² is hydrogen, C₁₋₆alkyl or together with R² ' forms a group (CH₂)_(q) where q is 2, 3 or 4and R¹³ is hydrogen, C₁₋₆ alkyl or an aryl group; or R¹ is a 5 to7-membered heterocyclic ring selected from the group consisting ofthienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl,thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl,pyrimidyl and pyrazinyl optionally substituted by C₁₋₆ alkyl;

R² and R³ are independently hydrogen, halogen, C₁₋₆ alkyl; C₃₋₆cycloalkenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkyl, C₁₋₆ alkylOC₁₋₆ alkyl,acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂ R¹⁰,CONR¹⁰ R¹¹, NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are independently hydrogen orC₁₋₆ alkyl, or R² and R³ together form a group --(CH₂)_(r) --R¹⁴--(CH₂)_(s) -- where R¹⁴ is O, S, CH₂ or NR¹⁵ where R¹⁵ is hydrogen orC₁₋₆ alkyl and r and s are independently 0, 1 or 2;

A is a group ##STR3## or a group ##STR4## where B is oxygen or sulphurand D is nitrogen, carbon or a CH group; and

R⁶ is hydrogen or C₁₋₆ alkyl and R⁷ is C₁₋₆ alkyl, C₁₋₆ alkoxy orhalogen, or R⁶ together with R⁷ forms a group --M-- where M is (CR¹⁶R¹⁷)_(t) where t is 1, 2 or 3 and R¹⁶ and R¹⁷ are independently hydrogenor C₁₋₆ alkyl or M is (CR¹⁶ R¹⁷)_(u) -J where u is 0, 1 or 2 and J isoxygen, sulphur, CR¹⁶ ═CR¹⁷, CR¹⁶ ═N, or N═N;

R⁸ is hydrogen or C₁₋₆ alkyl;

R⁹ and R¹⁰ are independently hydrogen or C₁₋₆ alkyl;

E is oxygen, CR¹⁸ R¹⁹ or NR²⁰ where R¹⁸, R¹⁹ and R²⁰ are independentlyhydrogen or C₁₋₆ alkyl or E is S(O)_(v) where v is 0, 1 or 2;

G is C═ or CR²¹ R²² where R²¹ and R²² are independently hydrogen or C₁₋₆alkyl;

X and Y are independently CR⁹ R¹⁰ where R⁹ and R¹⁰ are as defined above;and

m is 1, 2 or 3,

provided that P¹ and P² are not both phenyl.

C₁₋₆ alkyl groups, whether alone or as part of another group, may bestraight chain or branched.

When P¹ and P² are bicyclic heterocyclic rings suitable examples includequinoline, isoquinoline, benzofuran and benzothiophene. When P¹ and P²are monocyclic heterocyclic rings suitable examples include thienyl,furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl,oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyland pyrazinyl Preferably P¹ is phenyl. Preferably P² is a bicyclic arylring, in particular naphthyl. The P¹ and P² groups can be attached tothe remainder of the molecule at any suitable points.

Preferably R¹ is NR¹² COR¹³ or a 5-7 membered heterocyclic ring. When R¹is a 5 to 7-membered heterocyclic ring suitable examples includearomatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl,imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl,thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. Saturated and partiallysaturated rings are also within the scope of the invention, inparticular rings including an oxo or thioxo moiety such as lactams andthiolactams. The heterocyclic rings can be linked to the remainder ofthe molecule via a carbon atom or, when present, a nitrogen atom.Suitable substituents for these rings include R² and R³ groups asdefined above. Preferably R¹ is optionally substituted oxadiazolyl or anoptionally substituted lactam ring. Preferred substituents foroxadiazolyl groups include C₁₋₆ alkyl such as methyl. Most preferably R¹is a 5-methyl-1,3,4-oxadiazol-3-yl group or a 2-oxo-pyrrolidin-1-ylgroup.

Preferably R² and R³ are both hydrogen.

Preferably A is a group of formula (i).

Preferably B is oxygen.

Preferably D is nitrogen.

R⁶ together with R⁷ forms a group --M-- where M is (CR¹⁶ R¹⁷)_(t) wheret is 2 or 3 and R¹⁶ and R¹⁷ are both hydrogen.

Preferably R⁸ is hydrogen or methyl. Preferably m is 2 forming aspiro-piperidine ring,

Preferably R⁹ and R¹⁰ are both hydrogen.

Suitably E is oxygen, CR¹⁸ R¹⁹ or NR²⁰ where R¹⁸, R¹⁹ and R²⁰ areindependently hydrogen or C₁₋₆ alkyl or E is S(O)_(v) where v is 0, 1 or2. Preferably E is oxygen.

Suitably G is C═O or CR²¹ R²² where R²¹ and R²² are independentlyhydrogen or C₁₋₆ alkyl. Preferably G is CH₂.

Suitably X and Y are independently CR⁹ R¹⁰ where R⁹ and R¹⁰ are asdefined above. Preferably X and Y are both CH₂.

Particularly preferred compounds of the invention include:

5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}benzoyl]-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],

5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}benzoyl]-2,3,5,6,7,8-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine],

5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}-3-methylbenzoyl]-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],

5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}-3-methylbenzoyl]-2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine],

1'-Methyl-5-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],

5-[4-(2-Methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],

1'-Methyl-5-[6-(2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)nicotinoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],

or pharmaceutically acceptable salts and N-oxides thereof.

Preferred salts of the compounds of formula (I) are pharmaceuticallyacceptable salts. These include acid addition salts such ashydrochlorides, hydrobromides, phosphates. acetates, fumarates,maleates. tartrates. citrates. oxalates, methanesulphonates andp-toluenesulphonates.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and the mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the invention.

In a further aspect the present invention provides a process for thepreparation of a compound of formula (I) which comprises:

(a) for compounds of formula (I) where D is nitrogen and B is oxygen,reaction of a compound of formula (II): ##STR5## in which P¹, P², R¹,R², R² ' and R³ are as defined in formula (I);

with a compound of formula (III): ##STR6## wherein R⁶, R⁷, R⁸, R⁹, R¹⁰,E, G, X, Y, and m are as defined in formula (I and R²³ and

R²⁴ are functional groups which react together to form the A group; andoptionally thereafter in any order:

converting a compound of formula (I) into another compound of formula(I) forming a pharmaceutically acceptable salt.

Suitably one of R²³ or R²⁴ is --COL where L is a leaving group and theother is NHR⁶ where R⁶ is as defined above.

Suitable activated carboxylic acid derivatives of formula (II)/(III)include acyl halides and acid anhydrides. For example L can be chlorosuch that one of R²³ or R²⁴ is an acid chloride group COCl which can bereacted with a compound where R²³ or R²⁴ is NHR⁶. Activated compoundscan also be prepared by reaction of the corresponding carboxylic acidwith a coupling reagent such as carbonyldiimidazole,dicyclohexylcarbodiimide or diphenylphosphorylazide Preferably the groupL is halo, particularly chloro.

Compounds of formulae (II) and (III) are typically reacted together inan inert organic solvent such as DMF, THF or dichloromethane at ambientor elevated temperature in the presence of a base such as an alkalimetal hydroxide, triethylamine or pyridine.

Alternatively L is an ester forming group such that the resulting estersof formula (II) can be reacted with compounds of formula (III) in thepresence of an organo-aluminium reagent such as trimethylaluminium. Sucha reaction is typically carried out in the presence of an inert solventsuch as toluene.

Intermediate compounds of formula (II) and (III) can be prepared usingstandard procedures known in the art. Certain intermediate compounds offormula (II) and (III) are novel and form a further aspect of theinvention.

It will be appreciated to those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques can beused. For example, primary amines can be protected as phthalimide,benzyl, benzyloxycarbonyl or trityl derivatives. These groups can beremoved by conventional procedures well known in the art.

Carboxylic acid groups can be protected as esters. Aldehyde or ketonegroups can be protected as acetals, ketals. thioacetals or thioketals.Deprotection is achieved using standard conditions.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures known in the art. For exampleamino groups can be alkylated using base and an alkyl halide.

5HT_(1B) Antagonists, and in particular the compounds of the presentinvention, are expected to be of use in the treatment of CNS disorderssuch as mood disorders, including depression, seasonal effectivedisorder and dysthymia; anxiety disorders, including generalisedanxiety, panic disorder, agoraphobia, social phobia, obsessivecompulsive disorder and post-traumatic stress disorder; memorydisorders, including dementia, amnestic disorders and age-associatedmemory impairment; and disorders of eating behaviours, includinganorexia nervosa and bulimia nervosa. Other CNS disorders include motordisorders such as Parkinson's disease, dementia in Parkinson's disease,neuroleptic-induced Parkinsonism and tardive dyskinesias, as well asother psychiatric disorders.

5HT_(1B) Antagonists. and in particular compounds of the presentinvention, may also be of use in the treatment of endocrine disorderssuch as hyperprolactinaemia, in the treatment of vasospasm (particularlyin the cerebral vasculature) and hypertension, as well as disorders inthe gastrointestinal tract where changes in motility and secretion areinvolved. They may also be of use in the treatment of sexual dysfunctionand hypothermia.

Therefore, the present invention provides a compound of general formula(I) or a physiologically acceptable salt or solvate thereof for use intherapy.

The present invention also provides a compound of general formula (I) ora physiologically acceptable salt or solvate thereof for use in thetreatment of the aforementioned disorders.

In another aspect the invention provides the use of a compound ofgeneral formula (I) or a pharmaceutically acceptable salt or solvatethereof for the manufacture of a medicament for the treatment of theaforementioned disorders.

In a further aspect the invention provides a method of treating theaforementioned disorders which comprises administering an effectiveamount to a patient in need of such treatment of a compound of generalformula (I) or a pharmaceutically acceptable salt or solvate thereof.

In particular the invention provides a compound of general formula (I)or a physiologically acceptable salt or solvate thereof for use in thetreatment or prophylaxis of depression.

It will be appreciated by those skilled in the art that the compoundsaccording to the invention may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, differentantidepressant agents.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs. or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved. andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three a day. Such therapy mayextend for a number of weeks or months.

The following Examples illustrate the preparation of compounds of theinvention.

DESCRIPTION 1 Methyl 5-bromo-1-napthoate

5-Bromonapthoic acid (J Chem. Soc., 1950, 991) (5.13 g, 20 mmol) wasadded to a solution of thionyl chloride (10 ml) in methanol (200 ml).The mixture was stirred at reflux for 4 h, yielding a dark brownsolution. On cooling, the title compound precipitated as a light brownsolid, which was filtered off and dried, yielding 5.34 g material (98%).

¹ H NMR (200 MHz, CDCl₃) δ(ppm): 8.89 (d, 1H), 8.51 (d, 1H), 8.21 (d,1H), 7.85(d, 1H), 7.61 (dd, 1H), 7.44 (dd, 1H), 4.01 (s, 3H)

DESCRIPTION 2 5-Bromo-1-napthoic hydrazide

Methyl 5-bromo-1-naphthoate (D1) (5.32 g, 20 mmol) and hydrazine hydrate(5.7 ml, 100 mmol) were stirred at reflux in methanol (50 ml) for 48 h.After cooling, the solid was filtered off, washed with cold methanol,and dried in vacuo at 60° C., yielding the title compound (3.48 g, 65%)as a grey-brown crystalline powder.

¹ H NMR (250 MHz, d⁶ DMSO) δ(ppm): 9.77 (s, 1H), 8.24 (t, 2H), 7.95 (d,1H), 7.72 (t, 1H), 7.64 (d, 1H), 7.50 (t, 1H), 4.62 (s, 2H).

DESCRIPTION 3 2-(5-Bromo-1-naphthyl)-5-methyl-1,3,4-oxadiazole

5-Bromo-1-napthoic hydrazide (D2) (2.00 g, 7.5 mmol) was stirred atreflux under Ar in triethyl orthoacetate (20 ml) for 20 h. The mixturewas cooled in ice, and the solid was filtered off, washed with petroleumether (b.p. 60-80° C.), and dried in vacuo at 60° C., giving the titlecompound (1.92 g, 88%) as a light brown powder.

¹ H NMR (200 MHz, CDCl₃) δ(ppm): 9.26 (d, 1H), 8.49 (d, 1H), 8.18 (d,1H), 7.90 (d, 1H), 7.67 (t, 1H), 7.50 (t, 1H), 2.69 (s, 3H).

DESCRIPTION 41-(4-Carboxyphenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)naphthalene

2-(5-Bromo-1-naphthyl)-5-methyl-1,3,4-oxadiazole (D3) (1.50 g, 5.2 mmol)and 4-carboxyphenylboronic acid (0.86 g, 5.2 mmol) were stirred indimethoxyethane (DME) (40 ml), and sodium carbonate (2.5 g, 23 mmol) inwater (40 ml) was added. The mixture was purged by a stream of Ar for 15min, when tetrakis (triphenylphosphine)palladium (0) (0.1 g, 0.008 mmol)was added. The mixture was stirred at reflux under Ar for 20 h, and thenevaporated to remove DME. The grey suspension was acidified (5M HCl),and the solid was filtered off and dried in vacuo at 60° C. Thismaterial was heated at reflux in ethanol (30 ml), and filtered hot. Thewhite solid so collected was dried in vacuo at 60° C. giving 1.32 (77%)of the title compound.

¹ H NMR (250 MHz, d⁶ DMSO) δ(ppm): 9.15 (d, 1H), 8.19 (d, 1H), 8.12 (d,2H), 8.00 (d, 1H), 7.81 (t, 1H), 7.66 (t, 1H), 7.6 (m, 3H), 2.67 (s,3H).

DESCRIPTION 53-Methyl-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)naphth-1-yl]benzoic acid

The title compound was prepared from2-(5-bromo-1-naphthyl)-5-methyl-1,3,4-oxadiazole (D3, 395 mg; 1.36 mmol)and 4-borono-3-methylbenzoic acid (D3 in WO 96/19477,246 mg; 1.36 mmol)following a similar method to description 4, as a cream solid (305 mg,65%).

¹ H NMR (200 MHz, d⁶ DMSO) δ(ppm): 13.02 (s. 1H), 9.12 (d, 1H), 8.17 (d,1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.8 (t, 1H), 7.69-7.42 (m, 3H), 7.35 (d,1H), 2.65 (s, 3H), 2.0 (s, 3H).

DESCRIPTION 6 4-(6-Amino-2-methylpyridin-3-yl)benzoic acid hydrochloride

The title compound was prepared from 6-amino-3-bromo-2-methylpyridineusing a similar procedure to Description 4, as a grey solid (78%).

¹ H NMR (250 MHz, d⁶ DMSO) δ(ppm): 8.12 (br s, 2H), 8.02 (d, 2H), 7.88(d, 1H), 7.54 (d, 2H), 6.97 (d, 1H), 2.43 (s, 3H).

DESCRIPTION 7 Methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate

A stirred suspension of 4-(6-amino-2-methylpyridin-3-yl)benzoic acidhydrochloride (D6, 1.9 g, 8.3 mmole) in methanol (120 ml) was treatedwith conc. HCl acid (1 ml) and heated under reflux for 2 h. The solutionwas concentrated in vacuo, the residue treated with excess 10% Na₂ CO₃solution and extracted with ethyl acetate. The extract was dried (Na₂SO₄) and concentrated in vacuo to afford the title compound as a paleyellow solid (1.4 g, 70%).

¹ H NMR (200 MHz, d⁶ DMSO) δ(ppm): 7.98 (d, 2H), 7.45 (d, 2H), 7.30 (d,1H), 6.35 (d, 1H), 6.05 (br s, 2H), 3.87 (s, 3H), 2.25 (s, 3H).

DESCRIPTION 8 Methyl4[6-(4-chlorobutanoylamino)-2-methylpyridin-3-yl]benzoate

A stirred suspension of methyl 4-(6-amino-2-methylpyridin-3-yl)benzoate(D7, 1.0 g, 4.1 mmole) in dichloromethane (80 ml) was treated withpyridine (0.66 ml, 8.2 mmole), followed by 4-chlorobutyryl chloride(0.47 ml, 4.3 mmole). The resulting solution was stirred at 25° C. for 2h, then treated with 5% Na₂ CO₃ solution and after 30 minutes, theorganic layer was separated, dried (Na₂ SO₄) and concentrated in vacuoto leave a pale yellow solid. This was recrystallised from ethylacetate/60-80 petrol to afford the title compound as a beige solid (1.13g, 80%).

DESCRIPTION 9 Methyl4[2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]benzoate

A stirred solution of methyl4[6-(4-chlorobutanoylamino)-2-methylpyridin-3-yl]benzoate (D8, 0.60 g,1.7 mmole) in DMF (7 ml) at 25° C. under argon was treated portionwiseover 15 minutes with potassium t-butoxide (0.23 g, 2.0 mmole). Themixture was stirred for 3 h, then poured into water (100 ml) andextracted with ethyl acetate. The extract was washed with water, dried(Na₂ SO₄) and concentrated in vacuo to afford the title compound as anorange solid (0.45 g, 85%).

¹ H NMR (250 MHz, CDCl₃) δ(ppm): 8.26 (d, 1H), 8.10 (d, 2H), 7.55 (d,1H), 7.40 (d, 2H), 4.16 (t, 2H), 3.96 (s, 3H), 2.69 (t, 2H), 2.44 (s,3H), 2.15 (quintet, 2H).

DESCRIPTION 10 Methyl 6-(trifluoromethylsulphonyloxy)nicotinate

Methyl 6-hydroxynicotinate (J. Am. Chem. Soc., 1982, 1428-30) (9.00 g,0.058 mol) was dissolved in dry pyridine (150 ml) and was treated withtrifluoromethanesulphonic anhydride (10.73 ml, 0.064 mol), dropwise withstirring under argon with ice cooling. After 2 h, a further amount oftrifluoromethanesulphonic anhydride (2.68 ml, 0.016 mol) was added, andthe mixture was stirred for a further 1 h before being left standing atroom temp. overnight. The reaction mixture was then evaporated underreduced pressure, and the residue partitioned between dichloromethaneand sodium hydrogen carbonate solution. The organic layer was thenwashed with sodium hydrogen carbonate solution, dried (Na₂ SO₄) andevaporated under reduced pressure to give a brown oil, which wasazeotroped with toluene (2×) and dried in vacuo to give the titlecompound as a brown oil (1 1.07 g, 67%).

¹ H NMR (250 MHz, CDCl₃) δ(ppm): 9.00 (d, 1H), 8.51 (dd, 1H), 7.25 (d,1H), 3.98 (s, 3H).

DESCRIPTION 11 Methyl 6-(trimethylstannyl)nicotinate

Methyl 6-(trifluoromethylsulphonyloxy)nicotinate (D10, 3.89 g, 0.0136mol) was dissolved in dry dioxane (100 ml) and was treated with lithiumchloride (1.73 g, 0.041 mol), followed by 2,6-di-^(t)butyl-4-methylphenol (0.030 g), and hexamethyldistannane (5.00 g, 0.015mol). The mixture was flushed with argon andtetrakis(triphenylphosphine)palladium(0) (0.786 g, 0.007 mol) was added.The resulting mixture was then heated to reflux with stirring underargon. After 4 h, the reaction mixture was allowed to cool and was leftat room temperature overnight. The reaction mixture was then filteredthrough kieselguhr and the filter pad was washed with dichloromethane(70 ml). The filtrate was then evaporated under reduced pressure and theresidue was partitioned between diethyl ether and water. The organiclayer was then washed with 15% ammonia solution (2×), dried (Na₂ SO₄)and evaporated under reduced pressure to give the title compound as abrown oil, which was dried in vacuo (2.886 g, 71%).

¹ H NMR (200 MHz, CDCl₃) δ(ppm): 9.30 (d, 1H), 8.08 (dd, 1H), 7.54 (d,1H), 3.91 (s, 3H), 1.38 (s, 9H).

DESCRIPTION 12 Methyl6-[2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]nicotinate

Methyl 6-(trimethylstannyl)nicotinate (D11, 0.300 g, 1.00 mmol) wasdissolved in dry toluene (15 ml) and was treated with2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268A1)(0.211 g, 0.834 mmol). The mixture was flushed with argon andbis(triphenyl phosphine)pallalladium (II) chloride (0.029 g, 0.042 mmol)was added. The mixture was then heated to reflux under argon. After 2 h,further methyl 6-(trimethylstannyl)nicotinate (0.030 g, 0.100 mmol) intoluene (2 ml) and bis(triphenylphosphine) palladium (II) chloride(0.010 g, 0.014 mmol) was added. Reflux was continued for a further 2 hbefore the reaction mixture was allowed to cool. The reaction mixturewas then filtered through kieselguhr. The kieselguhr was washed withtoluene (2×20 ml) and the filtrate was evaporated under reduced pressureto give a yellow/brown solid which was dried in vacuo (0.450 g). Thesolid was then purified by silica-gel chromatography (1:1 Petrol 60-80:EtOAc as eluant) to give the title compound as a cream coloured solid(0.140 g, 54%).

¹ H NMR (250 MHz, CDCl₃) δ(ppm): 9.32 (d, 1H), 8.38 (dd, 1H), 8.03 (s,1H), 7.95 (d, 1H), 7.55 (m, 2H), 3.97 (s, 3H), 2.57 (s, 3H), 2.49 (s,3H).

EXAMPLE 15-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}benzoyl]-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]hydrochloride

1-(4-Carboxyphenyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)naphthalene (D4)(0.49 g, 0.45 mmol) in dichloromethane was treated with oxalyl chloride(0.047 ml, 0.53 mmol) followed by 1 drop of DMF. This mixture wasstirred under Ar for 1 h, washed with potassium carbonate/brinesolution, dried (Na₂ SO₄) and evaporated to give a white solid. This wasredissolved in dichloromethane (10 ml), and treated with1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine (D8in WO 96/19477, 0.100 g, 0.41 mmol) and triethylamine (0.09 ml, 0.65mmol). The mixture was stirred for 1 h, washed with potassiumcarbonate/brine solution, dried (Na₂ SO₄) and evaporated. The crudematerial was purified by chromatography on silica gel, eluting with0-10% methanol/dichloromethane. This gave the free base of the titlecompound (0.154 g, 67%) as white solid. This was dissolved indichloromethane, treated with 1M HCl in ether

(0.55 ml), and then diluted with ether (20 ml). This gave, afterfiltration and drying, the title compound (0.125 g) as a white solid.

¹ H NMR(200 MHz, d⁶ DMSO) δ(ppm): 10.32 (b, 1H), 9.16 (d, 1H), 8.23 (d,1H), 8.09 (d, 1H), 7.98 (b, 1H), 7.7-7.9 (m, 4H), 7.55-7.7 (m, 3H), 6.80(s, 1H), 4.53 (s, 2H), 4.12 (t, 2H), 3.45 (m, 2H), 3.0-3.2 (m, 4H), 2.80(bs, 3H), 2.68 (s, 3H), 2.2 (m, 2H), 1.91 (m, 2H).

EXAMPLE 25-[-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}benzoyl]-2,3,5,6,7,8-hexahydro-1'-methylspiro [furo[2,3-g]quinoline-3,4'-piperidinel]hydrochloride

Similar procedure to Example 1, using D4 and2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine](D10 in WO 96/19477).

¹ H NMR (200 MHz, d⁶ DMSO) δ(ppm): 10.6 (bs, 1H), 9.12 (d, 1H), 8.22 (d,1H), 8.11 (d, 1H), 7.8 (m, 2H), 7.59 (d, 1H), 7.44 (m, 4H), 6.69 (s,1H), 6.47 (b, 1H), 4.40 (s, 2H), 3.83 (m, 2H), 3.2 (m, 2H), 2.95 (m,2H), 2.7 (m, 5H), 2.67 (s, 3H), 1.75-2.1 (m, 4H), 1.55-1.7 (m, 2H).

EXAMPLE 35-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}-3-methylbenzoyl]-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]hydrochloride

The title compound was prepared from3-methyl-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl) naphth-1-yl]benzoic acid(D5, 150 mg; 0.436 mmol) and1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperldine] (D8in WO 96/19477, 106 mg; 0.43 mmol) following the procedure outlined inExample 1, as a white powder (96 mg, 36%).

¹ H NMR (free base) (200 MHz, CDCl₃) δ(ppm): 9.28 (d, 1H), 8.15 (d, 2H),7.8-7.61 m, 2H), 7.6-7.4 (m, 4H), 7.3 (d, 1H), 6.7 (s, 1H), 4.4 (s, 2H),4.29-4.1 (m, 2H), 3.1 (t, 2H), 2.95 (brs, 2H), 2.71 (s, 3H), 2.41 (s,3H), 2.3-2.0 (m, 7H), 1.96-1.72 (m, 2H).

EXAMPLE 45-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}-3-methylbenzoyl]-2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] hydrochloride

The title compound was prepared from3-methyl-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)naphth-1-yl]benzoic acid(D5, 125 mg; 0.363 mmol) and2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine](D10 in WO 96/19477, 94 mg; 0.363 mol) following the procedure outlinedin Example 1, as a white powder (88 mg, 39%).

¹ H NMR (free base) (200 MHz, CDCl₃) δ(ppm): 9.24 (d, 1H), 8.12 (d, 1H),7.73-7.55 (m, 2H), 7.46-7.25 (m, 3H), 7.1 (s, 2H), 6.6 (s, 1H), 6.5 (brs, 1H), 4.28 (s, 2H), 3.95 (t, 2H), 2.85-2.58 (m, 7H), 2.3 (s, 3H),2.13-1.85 (m, 7H), 1.8-1.45 (m, 4H).

EXAMPLE 51'-Methyl-5-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidinel]

A stirred solution of1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]-indole-3,4'-piperidine](D8 in WO 96/19477, 250 mg, 1.0 mmole) in toluene (15 ml) at 25° C.under argon was treated with trimethylaluminium (0.56 ml of 2M solutionin toluene, 1.1 mmole). After 15 minutes a solution of methyl4-[2'-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]benzoate (D9, 320 mg,1.0 mmole) in toluene (7 ml) was added and the mixture heated underreflux for 2 h. The reaction mixture was allowed to cool, then pouredinto a stirred slurry of silica gel (20 g) in dichloromethane (30 ml),stirred for 15 minutes, then loaded into a chromatography column andeluted with 0-10% methanol/dichloromethane. The title compound wasobtained as a yellow foam (163 mg, 31%), which was converted to itshydrochloride salt and crystallised from acetone/ether as a white solid.

¹ H NMR (free base) (250 MHz, CDCl₃) δ(ppm): 8.26 (d, 1H), 8.13 (br s,1H), 7.60 (d, 2H), 7.55 (d, 1H), 7.40 (d, 2H), 6.67 (s, 1H), 4.40 (br s,2H), 4.22-4.00 (m, 2H), 4.15 (t, 2H), 3.06 (t, 2H), 3.00-2.75 (br m,2H), 2.69 (t, 2H), 2.45 (s, 3H), 2.32 (br s, 3H), 2.25-160 (m, 6H), 2.13(quintet, 2H).

EXAMPLE 65-[4-(2-Methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]

1'-Methyl-5-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine](E5, 0.30 g, 0.59 mmol) was stirred under argon in 1,2-dichloroethane(20 ml) with dilsopropylethylamine (0.15 ml, 0.89 mmol) and1-chloroethyl chloroformate (0.16 ml, 1.5 mmol) for 16 h. The mixturewas concentrated in vacuo, and the residue was heated at reflux inmethanol (100 ml) for 1.5 h. The solution was evaporated to dryness, andthis residue was dissolved in dichloromethane, washed with 10% Na₂ CO₃,dried (Na₂ SO₄) and evaporated to dryness. The material was purified byconversion to the N-t-butoxycarbonyl derivative (di-t-butyldicarbonate,CH₂ Cl₂, 1h), chromatography, and deprotection with trifluoroacetic acidto afford the title compound. The hydrochloride salt was formed bydissolution in dichloromethane, treatment with 1 M HCl in Et₂ O, andtrituration in acetone. This gave 0. 123 g, 39% of a white powder.

¹ H NMR (HCl salt) (250 MHz, d⁶ DMSO) δ(ppm): 9.25 (d, 1H), 8.77 (d,1H), 8.22 (d, 1H) 7.97 (s, 1H), 7.72 (d, 1H), 7.68 (d, 2H), 7.51 (d,2H), 6.77 (s, 1H), 4.52 (s, 2H), 4.05 (t, 4H), 3.31 (bd, 2H), 3.04 (t,2H), 3.0 (m, 2H), 2.60 (t, 2H), 2.45 (s, 3H), 2.1 (m, 4H), 1.83 (bd,2H).

EXAMPLE 71'-Methyl-5-[6-(2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)nicotinoy]-2,3,6,7tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidinel]

1'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3.4'-piperidine] (D8in WO 96/19477, 0.092 g, 0.379 mmol) was dissolved in toluene (5 ml) andwas treated with trimethylaluminum (2.0 M in hexanes) (0.760 ml, 1.516mmol) with stirring under argon. After 15 minutes a suspension of methyl6-[2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl) phenyl]nicotinate (D12,0.130 g, 0.421 mmol) in toluene (14 ml) was added. The reaction mixturewas then heated to 80° C. with stirring. After 4 h, the reaction mixturewas allowed to cool and was left at room temperature overnight. Afurther amount of trimethylaluminium (2.0M in hexanes) (0.760 ml, 1.516mmol) was then added. The reaction mixture was then heated to refluxwith stirring. After 4 h, the reaction mixture was allowed to cool andwas poured into a slurry of silica-gel (9385˜10 g) in dichloromethane(50 ml). After effervescence had ceased, the reaction mixture wasfiltered and the filter pad washed with 20% MeOH/CH₂ Cl₂ (250 ml). Thefiltrate was then evaporated under reduced pressure to give a yellowsolid which was purified by silica-gel chromatography (7.5% MeOH/CH₂ Cl₂as eluant) to give the title compound as a yellow solid (0.020 g, 10%),which was converted to its oxalate salt, m.pt. 206-210° C.

¹ NMR (250 MHz, CDCl₃) (free base) δ(ppm): 8.91 (s, 1h), 8.91 (s, 1h),7.98 (m; 3h), 7.58 (m, 2h), 6.70 (s, 1h), 4.40 (s, 2h), 4.15 (m, 2h),3.12 (t, 2h), 2.92 (m2H), 2.6 (s, 3h), 2.48 (s, 3h), 2.40 (s, 3h), 2.15(m, 4h), 1.85 (m, 2h)

What is claimed is:
 1. A compound of formula (I) or a pharmaceuticallyacceptable salt or N-oxide thereof: ##STR7## in which P¹ and P² areindependently phenyl, napthyl, or pyridyl;R¹ is oxadiazolyl, or2-oxopyrrolidin-1-yl, unsubstituted or substituted by C₁₋₆ alkyl; R² andR³ are independently hydrogen, halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkyl,OC₁₋₆ alky, arylacyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂ R¹⁰, CONR¹⁰ R¹¹,NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are independently hydrogen or C₁₋₆ alkyl, orR² and R³ together form a group --(CH₂)_(r) --R¹⁴ --(CH₂)_(s) -- whereR¹⁴ is O, S, CH₂ or NR¹⁵ where R¹⁵ is hydrogen or C₁₋₆ alkyl and r and sare independently 0, 1 or 2; A is a group ##STR8## or a group ##STR9##where B is oxygen or sulphur and D is nitrogen, or a CH group; and R⁶together with R⁷ forms a group --M-- where M is (CR¹⁶ R¹⁷)_(t) where tis 2 or 3 and R¹⁶ and R¹⁷ are independently hydrogen or C₁₋₆ alkyl; R⁸is hydrogen or C₁₋₆ alkyl; R⁹ and R¹⁰ are independently hydrogen or C₁₋₆alkyl; E is oxygen, CR¹⁸ R¹⁹ or NR²⁰ where R¹⁸, R¹⁹ and R²⁰ areindependently hydrogen or C₁₋₆ alkyl or E is S(O)_(v) where v is 0, 1 or2; G is C═O or CR²¹ R²² where R²¹ and R²² are independently hydrogen orC₁₋₆ alkyl; X and Y are independently CR⁹ R¹⁰ where R⁹ and R¹⁰ are asdefined above; and m is 2;provided that P¹ and P² are not both phenyl.2. A compound according to claim 1 in which P² is naphthyl.
 3. Acompound according to claim 1 in which R² is C₁₋₆ alkyl.
 4. A compoundclaim 1 in which R⁴ is C₁₋₆ alkyl.
 5. A compound claim 1 in which n is 1and R⁵ and R⁶ are hydrogen.
 6. A compound according to claim 1 whichis:5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}benzoyl]-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}benzoyl]-2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine],5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}-3-methylbenzoyl]-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],5-[4-{5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-naphthyl}-3-methylbenzoyl]-2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine],1'-Methyl-5-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],5-[4-(2-Methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],1'-Methyl-5-[6-(2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)nicotinoyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],orpharmaceutically acceptable salts or N-oxides thereof.
 7. A process forthe preparation of a compound of formula (I) which comprises:(a) forcompounds of formula (I) where D is nitrogen and B is oxygen, reactionof a compound of formula (II): ##STR10## in which P¹, P², R¹, R² R² 'and R³ are as defined in formula (I);with a compound of formula (III):##STR11## wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, E, G, X, Y, and m are as definedin formula (I) and R²³ and R²⁴ are functional groups which reacttogether to form the A group;and optionally thereafter in any order:converting a compound of formula (I) into another compound of formula(I) forming a pharmaceutically acceptable salt.
 8. A pharmaceuticalcomposition which comprises a 5HT1B receptor antagonistic effectiveamount of a compound according to claim 1 in association with apharmaceutically acceptable carrier or excipient.